Villa Erica, Lei Barbara, Taliani Gloria, Graziosi Amalia, Critelli Rosina, Luongo Monica, Gennari William, Bianchini Marcello, Ferretti Ilva
Gastroenterology Unit, Azienda Ospedaliero-Universitaria, University of Modena and Reggio Emilia, Modena, Italy.
Antivir Ther. 2009;14(8):1081-7. doi: 10.3851/IMP1465.
In patients with advanced fibrosis, primary end points of long-term or possibly indefinite antiviral therapy are sustained inhibition of viral replication and avoidance of emergence of resistance. In lamivudine-treated patients, the strongest predictor of emergence of YMDD mutations is baseline hepatitis B virus (HBV) DNA viral load. We aimed to verify whether abatement of viraemia by a short course of pegylated interferon (PEG-IFN-alpha2a) treatment before lamivudine treatment could prevent the emergence of lamivudine-associated mutations during long-term therapy.
A total of 14 patients with hepatitis B e antigen (HBeAg)-negative infection (3 lamivudine-experienced and 11 lamivudine-naive), with moderate/high viraemia (>10(6) copies/ml) and with Ishak stage 4-6 at liver biopsy were sequentially treated with 180 microg PEG-IFN-alpha2a for a period long enough to reach HBV DNA levels < or =10(3) copies/ml or have a decrease of 3 log(10) copies/ml from baseline. Lamivudine was then added to PEG-IFN-alpha2a treatment for 1 month and finally continued as monotherapy for 2 years or until viral breakthrough.
Baseline HBV DNA (mean +/-se 2.3 x 10(7) +/-7.2 x 10(7) copies/ml) decreased with PEG-IFN-alpha2a treatment to target value in mean +/-se 3.7 +/-1.3 months. None of the 11 lamivudine-naive patients developed genotypic resistance and were still HBV-DNA-negative after a mean +/-se observation period of 23 +/-2 months, whereas the three lamivudine-experienced patients developed YMDD mutations after 6, 9 and 12 months of lamivudine monotherapy (P=0.003, Fisher's exact test).
In lamivudine-naive patients, abatement of HBV DNA<10(3) copies/ml by pretreatment with PEG-IFN-alpha2a completely prevents the emergence of YMDD mutants after 24 months of lamivudine monotherapy. This sequential schedule can optimize the use of a well tolerated, effective and inexpensive drug, such as lamivudine, in highly viraemic HBV patients.
在晚期纤维化患者中，长期或可能无限期抗病毒治疗的主要终点是持续抑制病毒复制和避免耐药性的出现。在接受拉米夫定治疗的患者中，YMDD突变出现的最强预测因素是基线乙型肝炎病毒（HBV）DNA病毒载量。我们旨在验证在拉米夫定治疗前通过短期聚乙二醇化干扰素（PEG-IFN-α2a）治疗降低病毒血症是否能预防长期治疗期间拉米夫定相关突变的出现。
共有14例乙型肝炎e抗原（HBeAg）阴性感染患者（3例曾接受拉米夫定治疗，11例未接受过拉米夫定治疗），病毒血症中度/高度（>10⁶拷贝/ml），肝活检Ishak分期为4 - 6期，先后接受180μg PEG-IFN-α2a治疗，治疗时间足够长以达到HBV DNA水平≤10³拷贝/ml或较基线下降3 log₁₀拷贝/ml。然后在PEG-IFN-α2a治疗中加用拉米夫定1个月，最后继续单药治疗2年或直至病毒突破。
PEG-IFN-α2a治疗后，基线HBV DNA（均值±标准差2.3×10⁷±7.2×10⁷拷贝/ml）在平均±标准差3.7±1.3个月降至目标值。11例未接受过拉米夫定治疗的患者中无一例发生基因型耐药，在平均±标准差23±2个月的观察期后仍为HBV-DNA阴性，而3例曾接受拉米夫定治疗的患者在拉米夫定单药治疗6、9和12个月后发生YMDD突变（P = 0.003，Fisher精确检验）。
在未接受过拉米夫定治疗的患者中，PEG-IFN-α2a预处理使HBV DNA降至<10³拷贝/ml可完全预防拉米夫定单药治疗24个月后YMDD突变体的出现。这种序贯方案可优化在高病毒血症HBV患者中使用耐受性良好、有效且廉价的药物，如拉米夫定。
